1. Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes
- Author
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Amy W Ku, Jason B Muhitch, Colin A Powers, Michael Diehl, Minhyung Kim, Daniel T Fisher, Anand P Sharda, Virginia K Clements, Kieran O'Loughlin, Hans Minderman, Michelle N Messmer, Jing Ma, Joseph J Skitzki, Douglas A Steeber, Bruce Walcheck, Suzanne Ostrand-Rosenberg, Scott I Abrams, and Sharon S Evans
- Subjects
myeloid-derived suppressor cells ,T cell trafficking ,lymph node ,L-selectin ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.
- Published
- 2016
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